TOXICOLOGICAL PROFILE FOR CHLORINE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service
Agency for Toxic Substances and Disease Registry
November 2010
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DISCLAIMER
The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry.
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UPDATE STATEMENT
A Toxicological Profile for Chlorine, Draft for Public Comment was released in October 2007. This edition supersedes any previously released draft or final profile.
Toxicological profiles are revised and republished as necessary. For information regarding the update status of previously released profiles, contact ATSDR at:
Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
1600 Clifton Road NE Mailstop F-62
Atlanta, Georgia 30333
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FOREWORD
This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary.
The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for these toxic substances described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced.
The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR.
Each profile includes the following:
(A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a toxic substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects;
(B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and
(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans.
The principal audiences for the toxicological profiles are health professionals at the Federal, State, and local levels; interested private sector organizations and groups; and members of the public.
This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR.
Thomas R. Frieden, M.D., M.P.H. Administrator
Agency for Toxic Substances and Disease Registry
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*Legislative Background
The toxicological profiles are developed under the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health related authorities” of the statute. This includes the preparation of toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for substances not found at sites on the National Priorities List, in an effort to “…establish and maintain inventory of literature, research, and studies on the health effects of toxic substances” under CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise necessary to support the site-specific response actions conducted by ATSDR.
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QUICK REFERENCE FOR HEALTH CARE PROVIDERS
Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions.
Primary Chapters/Sections of Interest
Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance’s relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure.
Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, and assesses the significance of toxicity data to human health.
Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure.
Pediatrics: Four new sections have been added to each Toxicological Profile to address child health issues: Section 1.6 How Can (Chemical X) Affect Children? Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? Section 3.7 Children’s Susceptibility Section 6.6 Exposures of Children
Other Sections of Interest: Section 3.8 Biomarkers of Exposure and Effect Section 3.11 Methods for Reducing Toxic Effects
ATSDR Information Center Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 E-mail: [email protected] Internet: http://www.atsdr.cdc.gov
The following additional material can be ordered through the ATSDR Information Center:
Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity; and numerous chemical-specific case studies.
http:http://www.atsdr.cdc.govmailto:[email protected]
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Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are planning guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume III— Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care professionals treating patients exposed to hazardous materials.
Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances.
Other Agencies and Organizations
The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, injury, and disability related to the interactions between people and their environment outside the workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015.
The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational diseases and injuries, responds to requests for assistance by investigating problems of health and safety in the workplace, recommends standards to the Occupational Safety and Health Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 • Phone: 800-35-NIOSH.
The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for biomedical research on the effects of chemical, physical, and biologic environmental agents on human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, Research Triangle Park, NC 27709 • Phone: 919-541-3212.
Referrals
The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics in the United States to provide expertise in occupational and environmental issues. Contact: AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 • FAX: 202-347-4950 • e-mail: [email protected] • Web Page: http://www.aoec.org/.
The American College of Occupational and Environmental Medicine (ACOEM) is an association of physicians and other health care providers specializing in the field of occupational and environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266.
http:http://www.aoec.orgmailto:[email protected]
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CONTRIBUTORS
CHEMICAL MANAGER(S)/AUTHOR(S):
G. Daniel Todd, Ph.D. Patricia Ruiz, Ph.D. Larry Cseh, R.S. Pam Tucker, M.D. John Doyle, M.P.A. ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
Fernando T. Llados, Ph.D. Daniel J. Plewak, B.S. Mario Citra, Ph.D. SRC, Inc., North Syracuse, NY
THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:
1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points.
2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs.
3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure consistency across profiles and adherence to instructions in the Guidance.
4. Green Border Review. Green Border review assures the consistency with ATSDR policy.
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PEER REVIEW
A peer review panel was assembled for chlorine. The panel consisted of the following members:
1. John Balmes, M.D., Professor in Residence, Department of Medicine, University of California, San Francisco, San Francisco, California;
2. Meryl Karol, Ph.D., Professor Emeritus, Associate Dean for Academic Affairs and Research, University of Pittsburgh, Pittsburgh, Pennsylvania; and
3. Dennis Shusterman, M.D., MPH, Professor Emeritus, Department of Medicine, University of California, San Francisco, California.
These experts collectively have knowledge of chlorine's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended.
Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound.
The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR.
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CONTENTS
DISCLAIMER ..............................................................................................................................................ii UPDATE STATEMENT .............................................................................................................................iii FOREWORD ................................................................................................................................................ v QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii CONTRIBUTORS....................................................................................................................................... ix PEER REVIEW ...........................................................................................................................................xi CONTENTS...............................................................................................................................................xiii LIST OF FIGURES ..................................................................................................................................xvii LIST OF TABLES.....................................................................................................................................xix
1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1 1.1 WHAT IS CHLORINE?................................................................................................................. 2 1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT? ................... 2 1.3 HOW MIGHT I BE EXPOSED TO CHLORINE?........................................................................ 3 1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY?..................................................... 3 1.5 HOW CAN CHLORINE AFFECT MY HEALTH?...................................................................... 4 1.6 HOW CAN CHLORINE AFFECT CHILDREN? ......................................................................... 5 1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CHLORINE? ..................... 5 1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
TO CHLORINE?............................................................................................................................ 6 1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? ................................................................................................... 6 1.10 WHERE CAN I GET MORE INFORMATION?.......................................................................... 7
2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9 2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE
UNITED STATES ......................................................................................................................... 9 2.2 SUMMARY OF HEALTH EFFECTS......................................................................................... 10 2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 14
3. HEALTH EFFECTS.............................................................................................................................. 25 3.1 INTRODUCTION........................................................................................................................ 25 3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 25
3.2.1 Inhalation Exposure .............................................................................................................. 26 3.2.1.1 Death.............................................................................................................................. 26 3.2.1.2 Systemic Effects............................................................................................................. 46 3.2.1.3 Immunological and Lymphoreticular Effects ................................................................ 70 3.2.1.4 Neurological Effects ...................................................................................................... 71 3.2.1.5 Reproductive Effects...................................................................................................... 73 3.2.1.6 Developmental Effects................................................................................................... 73 3.2.1.7 Cancer ............................................................................................................................ 74
3.2.2 Oral Exposure........................................................................................................................ 75 3.2.2.1 Death.............................................................................................................................. 75 3.2.2.2 Systemic Effects............................................................................................................. 76 3.2.2.3 Immunological and Lymphoreticular Effects ................................................................ 96 3.2.2.4 Neurological Effects ...................................................................................................... 97 3.2.2.5 Reproductive Effects...................................................................................................... 97 3.2.2.6 Developmental Effects................................................................................................... 98 3.2.2.7 Cancer ............................................................................................................................ 98
3.2.3 Dermal Exposure................................................................................................................. 100 3.2.3.1 Death............................................................................................................................ 100 3.2.3.2 Systemic Effects........................................................................................................... 100 3.2.3.3 Immunological and Lymphoreticular Effects .............................................................. 104 3.2.3.4 Neurological Effects .................................................................................................... 104 3.2.3.5 Reproductive Effects.................................................................................................... 104 3.2.3.6 Developmental Effects................................................................................................. 104 3.2.3.7 Cancer .......................................................................................................................... 104
3.3 GENOTOXICITY ...................................................................................................................... 105 3.4 TOXICOKINETICS................................................................................................................... 107
3.4.1 Absorption........................................................................................................................... 107 3.4.1.1 Inhalation Exposure ..................................................................................................... 107 3.4.1.2 Oral Exposure .............................................................................................................. 109 3.4.1.3 Dermal Exposure ......................................................................................................... 109
3.4.2 Distribution ......................................................................................................................... 109 3.4.2.1 Inhalation Exposure ..................................................................................................... 109 3.4.2.2 Oral Exposure .............................................................................................................. 109 3.4.2.3 Dermal Exposure ......................................................................................................... 110
3.4.3 Metabolism.......................................................................................................................... 110 3.4.4 Elimination and Excretion................................................................................................... 110
3.4.4.1 Inhalation Exposure ..................................................................................................... 110 3.4.4.2 Oral Exposure .............................................................................................................. 110 3.4.4.3 Dermal Exposure ......................................................................................................... 111
3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 111 3.5 MECHANISMS OF ACTION ................................................................................................... 112
3.5.1 Pharmacokinetic Mechanisms............................................................................................. 112 3.5.2 Mechanisms of Toxicity...................................................................................................... 114 3.5.3 Animal-to-Human Extrapolations ....................................................................................... 115
3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................... 115 3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................ 117 3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 120
3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine......................................... 121 3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine........................................... 122
3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 122 3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................ 122 3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................ 124
3.11.1 Reducing Peak Absorption Following Exposure............................................................. 124 3.11.2 Reducing Body Burden ................................................................................................... 125 3.11.3 Interfering with the Mechanism of Action for Toxic Effects .......................................... 125
3.12 ADEQUACY OF THE DATABASE..................................................................................... 126 3.12.1 Existing Information on Health Effects of Chlorine........................................................ 126 3.12.2 Identification of Data Needs............................................................................................ 130 3.12.3 Ongoing Studies .............................................................................................................. 139
4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 143 4.1 CHEMICAL IDENTITY............................................................................................................ 143 4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................... 143
5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 151 5.1 PRODUCTION .......................................................................................................................... 151 5.2 IMPORT/EXPORT .................................................................................................................... 152
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5.3 USE ............................................................................................................................................ 152 5.4 DISPOSAL................................................................................................................................. 158
6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 159 6.1 OVERVIEW............................................................................................................................... 159 6.2 RELEASES TO THE ENVIRONMENT................................................................................... 160
6.2.1 Air ....................................................................................................................................... 160 6.2.2 Water ................................................................................................................................... 163 6.2.3 Soil ...................................................................................................................................... 164
6.3 ENVIRONMENTAL FATE ...................................................................................................... 164 6.3.1 Transport and Partitioning................................................................................................... 164 6.3.2 Transformation and Degradation ........................................................................................ 165
6.3.2.1 Air ................................................................................................................................ 165 6.3.2.2 Water............................................................................................................................ 166 6.3.2.3 Sediment and Soil ........................................................................................................ 167 6.3.2.4 Other Media ................................................................................................................. 167
6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT.................................. 167 6.4.1 Air ....................................................................................................................................... 168 6.4.2 Water ................................................................................................................................... 168 6.4.3 Sediment and Soil ............................................................................................................... 168 6.4.4 Other Environmental Media................................................................................................ 168
6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ........................................ 169 6.6 EXPOSURES OF CHILDREN.................................................................................................. 170 6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 170 6.8 ADEQUACY OF THE DATABASE ........................................................................................ 171
6.8.1 Identification of Data Needs ............................................................................................... 172 6.8.2 Ongoing Studies .................................................................................................................. 174
7. ANALYTICAL METHODS................................................................................................................ 177 7.1 BIOLOGICAL MATERIALS.................................................................................................... 177 7.2 ENVIRONMENTAL SAMPLES .............................................................................................. 177 7.3 ADEQUACY OF THE DATABASE ........................................................................................ 179
7.3.1 Identification of Data Needs ............................................................................................... 182 7.3.2 Ongoing Studies .................................................................................................................. 183
8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 185
9. REFERENCES .................................................................................................................................... 191
10. GLOSSARY ...................................................................................................................................... 213
APPENDICES A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 B. USER’S GUIDE.................................................................................................................................. B-1 C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1 D. INDEX ................................................................................................................................................D-1
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LIST OF FIGURES
3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 42
3-2. Levels of Significant Exposure to Hypochlorite Solution – Oral ....................................................... 88
3-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance.................................................................................................... 113
3-4. Existing Information on Health Effects of Chlorine Gas ................................................................. 127
3-5. Existing Information on Health Effects of Hypochlorite Solution ................................................... 128
4-1. Speciation of Cl2, HOCl, and OCl- as a Function of pH................................................................... 148
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LIST OF TABLES
3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 30
3-2. Acute Effects of Chlorine Exposure on the Respiratory Tract of Humans......................................... 47
3-3. Levels of Significant Exposure to Hypochlorite Solution – Oral ....................................................... 77
3-4. Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite Chlorine - Dermal............................................................................................................................. 101
3-5. Genotoxicity of Sodium Hypochlorite In Vivo ................................................................................. 106
3-6. Genotoxicity of Sodium Hypochlorite In Vitro ................................................................................ 108
4-1. Chemical Identity of Chlorine .......................................................................................................... 144
4-2. Commonly Used Terms Related to Chlorinated Water .................................................................... 145
4-3. Physical and Chemical Properties of Chlorine ................................................................................. 146
5-1. Companies that Produce Chlorine in the United States and Annual Capacities for 2006 ................ 153
5-2. Facilities that Produce, Process, or Use Chlorine............................................................................. 155
5-3. U.S. Chlorine Imports and Exports by Year in Metric Tons ............................................................ 157
6-1. Releases to the Environment from Facilities that Produce, Process, or Use Chlorine ..................... 161
6-2. Ongoing Studies Regarding the Potential for Human Exposure to Chlorine ................................... 175
7-1. Analytical Methods for Determining Chlorine in Environmental Samples...................................... 180
8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and Chlorine Compounds .......... 187
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1. PUBLIC HEALTH STATEMENT
This public health statement tells you about chlorine and the effects of exposure to it.
The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the
nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term
federal clean-up activities. Chlorine gas is too reactive to be detected in environmental media at
hazardous waste sites. Any chlorine gas released at these sites would be quickly converted to other
substances whose primary source may or may not have been chlorine.
When a substance is released either from a large area, such as an industrial plant, or from a container,
such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You
can be exposed to a substance only when you come in contact with it. You may be exposed by breathing,
eating, or drinking the substance, or by skin contact. Since chlorine is highly reactive, you are unlikely to
be exposed directly to it unless there has been a large scale accidental release in the nearby vicinity.
If you are exposed to chlorine, many factors will determine whether you will be harmed. These factors
include the dose (how much), the duration (how long), and how you come in contact with it. You must
also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and
state of health.
The subject of this profile is molecular chlorine (Cl2), which exists as a gas under normal environmental
conditions or as a liquid when stored under pressure. Although molecular chlorine is used in some water
disinfection processes, the resulting solution, commonly referred to as chlorinated water, does not actually
contain molecular chlorine. Therefore, water disinfection and the chemicals present in chlorinated water,
such as hypochlorite, are not the main focus of this document and are only discussed where relevant.
CHLORINE 2
1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS CHLORINE?
Chlorine is a gas with a very irritating odor
It is very unstable and quickly reacts with many substances to form other chemicals.
Used in Chlorine is an extremely important industrial chemical that is used in the manufacturing production of thousands of products. and water disinfection It is also used for water disinfection, although the chlorine itself is quickly
transformed into other chemicals at the beginning of the process.
Chlorine gas is A common misconception is that molecular chlorine (Cl2) is present in not present in chlorinated water. During water chlorination, molecular chlorine gas may be chlorinated water added to the water at first; however, the chlorine is quickly transformed into
other chemicals, which actually disinfect the water. Hypochlorous acid and hypochlorite anion are two of these chemicals that disinfect the water.
The terms “free chlorine” and “aqueous chlorine” in drinking water usually refer to the amount of hypochlorous acid and hypochlorite in the water. It is important to recognize that these compounds are different from molecular chlorine.
Bleach is not One of the important products that chlorine is used to make is bleach, and chlorine people sometimes confuse chlorine with bleach. Bleach contains a
compound called sodium hypochlorite. If you mix acidic chemicals with bleach, chlorine can be formed and given off as a gas.
For more information on the sources, properties, and uses of chlorine, see Chapters 4 and 5.
1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT?
Chlorine is very unstable in the environment
Chlorine is very unstable, and reacts with a variety of chemicals and water when it is released into the environment.
Rapidly broken down
• Air
• Water
Chlorine is broken down by sunlight within a matter of several minutes.
Chlorine dissolves in water and is converted into chloride and hypochlorous acid.
Chlorine can travel from its source
If chlorine is spilled into water or onto soil or if it is released from a tank into the air, the chlorine will evaporate very quickly forming a greenish-yellow cloud that can be carried by the wind from the source.
For more information on chlorine in the environment, see Chapter 6.
CHLORINE 3
1. PUBLIC HEALTH STATEMENT
1.3 HOW MIGHT I BE EXPOSED TO CHLORINE?
Most people are not expected to be exposed to chlorine
Because chlorine is so reactive, it is not normally detected in the environment except for very low levels in the air above seawater.
Accidental You may be exposed through breathing, skin contact, and eye contact if an exposure to accident involving chlorine takes place nearby, such as a liquid chlorine spill, chlorine a leak from a chlorine tank, or a leak from a facility that produces or uses
chlorine.
You may also be exposed to chlorine if you mix household chemicals such as toilet cleaner with bleach.
Hypochlorous acid is used to treat swimming pool water. You may be exposed to chlorine gas through the improper use of swimming pool chemicals.
Workplace air People who work in places where chlorine is made or used may be exposed to low levels over a period of time.
People may be exposed to high levels if a large amount of chlorine is released during an accident.
For more information on human exposure to chlorine, see Chapter 6.
1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY?
Chlorine gas enters your body only when you breathe it in.
Chlorine gas can enter your body through your nose or your mouth.
At low concentrations (less than 10 ppm), almost all of the chlorine is removed from the air in the upper part of the respiratory airways and only a very small amount may reach your lungs.
If you drink hypochlorite solution, it may react with the acids in your stomach and possibly form chlorine gas.
Immediately reacts with other chemicals
Chlorine gas reacts with the water in the cells located in the surface of the respiratory airways and forms other compounds that produce irritation of the airways.
Most of these compounds eventually are transformed into chloride ions, which are normal components of the body.
For more information on how chlorine enters and leaves the body, see Chapter 3.
CHLORINE 4
1. PUBLIC HEALTH STATEMENT
1.5 HOW CAN CHLORINE AFFECT MY HEALTH?
This section looks at studies concerning potential health effects in animal and human studies.
The effect of chlorine on human health depends on how much chlorine is present, how you are exposed to
it, and the length of exposure.
Short-term exposure to chlorine in air
The following effects have been observed in humans briefly exposed to chlorine:
• mild nose irritation at 1–3 ppm • eye irritation at 5 ppm • throat irritation at 5–15 ppm • immediate chest pain, vomiting, changes in breathing rate, and
cough at 30 ppm • lung injury (toxic pneumonitis) and pulmonary edema (fluid in the
lungs) at 40–60 ppm • death after 30 minute exposure to 430 ppm • death after a few minute exposure to 1,000 ppm
The concentrations listed above are approximate; the effects will depend also on exposure duration. In general, people who suffer from respiratory conditions such as allergies or hay fever, or who are heavy smokers, tend to experience more severe effects than healthy subjects or nonsmokers.
Long-term exposure to chlorine in air
No significant harmful health effects were observed in workers exposed for years to relatively low concentrations of chlorine (around 1 ppm).
The tissues inside the nose were principally affected in animals exposed to chlorine for longer durations.
Short-term exposure to hypochlorite solution by ingestion
Drinking small amounts of hypochlorite solution (less than a cup) can produce irritation of the esophagus. Drinking concentrated hypochlorite solution can produce severe damage to the upper digestive tract and even death. These effects are most likely caused by the caustic nature of the hypochlorite solution and not from exposure to molecular chlorine.
Long-term exposure to hypochlorite solution by ingestion
There is no information on long-term ingestion of hypochlorite solution in humans. Animals that drank hypochlorite solution in water for up to 2 years did not show any significant health effects. The amount of hypochlorite solution in the water that the animals drank was much smaller than what is found in household bleach.
Skin exposure to hypochlorite solution
Spilling hypochlorite solution on the skin can produce irritation. The severity of the effects depends on the concentration of sodium hypochlorite in the bleach.
Further information on the health effects of chlorine in humans and animals can be found in Chapters 2
and 3.
CHLORINE 5
1. PUBLIC HEALTH STATEMENT
1.6 HOW CAN CHLORINE AFFECT CHILDREN?
This section discusses potential health effects in humans from exposures during the period from
conception to maturity at 18 years of age.
Children are likely to have similar effects as adults, but may be more sensitive than adults
Short-term exposures (minutes) to high concentrations of chlorine affect children in the same manner they affect adults (i.e., mucous membrane and respiratory tract irritation). We do not know what the effects could be in children following longer-term (weeks or longer), low-level exposure to chlorine gas, but this type of exposure occurs only in workers and is not relevant to children. We also do not know what the effects could be in children following longer-term, low-level exposure to hypochlorite solution.
Birth defects We do not know whether exposure to chlorine gas during pregnancy can result in damage to unborn babies because there are no studies of pregnant women or pregnant animals exposed to chlorine gas.
One study of rats exposed to hypochlorite solution during pregnancy found no evidence of birth defects or any other developmental alteration in the baby rats. The amount of chlorine that the rats consumed was many times higher than what people are normally exposed to through drinking water.
1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CHLORINE?
Do not mix bleach with household cleaners
Chlorine gas can be released to the air when bleach is mixed with other cleaning solutions that contain an acid like some toilet cleaners. Mixing bleach with ammonia also produces very hazardous gases, such as chloramines.
Store household chemicals out of reach of young children
Always store household chemicals in their original labeled containers out of reach of young children to prevent accidental poisonings. Never store household chemicals in containers children would find attractive to eat or drink from, such as old soda bottles.
Follow instructions for swimming pool disinfection
Chlorine gas can also be released to the air when chemicals used to chlorinate swimming pools are mishandled. If you have a swimming pool at home, read the labels of the chlorination products carefully and do not let children play with these products.
CHLORINE 6
1. PUBLIC HEALTH STATEMENT
1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO CHLORINE?
There are no medical tests available for chlorine
There are no medical tests to determine whether you have been exposed specifically to chlorine.
Chlorine is transformed in the body into chloride ions, which are normal components of the body. An enormous amount of chlorine has to be inhaled or ingested in order to detect a significant increase in chloride ions in the blood. This has occurred in a few cases of ingestion of large amounts of hypochlorite solution and one of them was a fatal case.
1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH?
The federal government develops regulations and recommendations to protect public health. Regulations
can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the
Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic
substances. Recommendations provide valuable guidelines to protect public health, but cannot be
enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National
Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop
recommendations for toxic substances.
Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic
substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that
affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-to-
exceed levels differ among federal organizations because they used different exposure times (an 8-hour
workday or a 24-hour day), different animal studies, or other factors.
Recommendations and regulations are also updated periodically as more information becomes available.
For the most current information, check with the federal agency or organization that provides it.
7 CHLORINE
1. PUBLIC HEALTH STATEMENT
Some regulations and recommendations for chlorine include the following:
Levels in air set by EPA
EPA established an environmental air limit of 0.5 ppm. Exposure to higher levels could result in discomfort and irritation. Dependent on the concentration, these effects may be reversible when exposure ends.
Levels in workplace air set by OSHA
OSHA set a legal limit of 1 ppm chlorine in air as a ceiling limit. At no time should a worker’s exposure exceed this limit.
Levels in drinking water set by EPA
EPA established a maximum contaminant level (MCL) and maximum residual disinfectant level (MRDL) of 4 mg/L for free chlorine in drinking water.
1.10 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns, please contact your community or state health or
environmental quality department, or contact ATSDR at the address and phone number below.
ATSDR can also tell you the location of occupational and environmental health clinics. These clinics
specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous
substances.
Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may
request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical
assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at [email protected], or by writing
to:
Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine 1600 Clifton Road NE Mailstop F-62 Atlanta, GA 30333 Fax: 1-770-488-4178
mailto:[email protected]:www.atsdr.cdc.gov
8 CHLORINE
1. PUBLIC HEALTH STATEMENT
Organizations for-profit may request copies of final Toxicological Profiles from the following:
National Technical Information Service (NTIS) 5285 Port Royal Road Springfield, VA 22161 Phone: 1-800-553-6847 or 1-703-605-6000 Web site: http://www.ntis.gov/
http:http://www.ntis.gov
9 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE UNITED STATES
Chlorine is a greenish-yellow gas with a pungent, irritating odor. It is stored and transported as a liquid
under pressure. Chlorine is transported as either a liquid or a gas through pipelines within chemical plants
or over distances of several kilometers. When chlorine is released into the environment, it reacts with
both organic and inorganic substances that it comes into contact with. When chlorine gas is released into
water, such as during water chlorination, it quickly dissolves in the water and then disproportionates
within seconds to form chloride and hypochlorous acid. Chlorine may be released into the environment
from facilities where it is produced or used, or during accidents, such as a chlorine tank rupture or a liquid
chlorine spill. Most of the chlorine released during these types of incidents is expected to volatilize into
the air forming a greenish-yellow chlorine gas cloud. Because chlorine is approximately 2.5 times
heavier than air, the chlorine cloud remains near the ground. This cloud can be carried away from the site
of release by the wind. Chlorine undergoes direct photolysis in the air and its half-life in the troposphere
is on the order of several minutes.
Because it is so reactive, chlorine gas is normally not detected in the environment except at low levels in
seawater aerosols. Therefore, background exposure of the general population to chlorine is not expected
to represent a health concern. Human biomonitoring data are not available for chlorine. Analyzing
human biological tissue and fluids for chlorine is not relevant because >95% of the chlorine that is
inhaled (over a 1–5 ppm range) is removed in the upper respiratory tract and eventually joins the chloride
pool in the body. The amount of chlorine that would need to be inhaled to induce a significant increase in
extracellular chloride in the body is probably a lethal amount.
There are two primary means by which the general population may be exposed to chlorine. Individuals
located near an accidental release of chlorine, either from a manufacturing facility or the transportation of
liquefied chlorine may be exposed to high levels of this gas through inhalation and dermal contact if the
cloud travels in their direction. In addition, people who mix acidic solutions with hypochlorite solutions,
such as bleach or certain types of swimming pool chemicals, may accidentally be exposed to chlorine gas.
Children may be exposed to chlorine through the same routes that affect adults, except for occupational
exposures. Occupational exposure to low levels of chlorine gas in air may occur for individuals who
work at facilities that produce or use chlorine. These individuals may also be exposed to high chlorine
concentrations if an accidental release occurs inside the facility.
10 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
Exposure to chlorine through drinking water is expected to be very low. Free chlorine in drinking water
is defined as the sum of dissolved chlorine gas, hypochlorous acid, and hypochlorite anion. As discussed
in Chapters 4 and 6, the level of dissolved chlorine in water is extremely low, except under acidic
conditions; therefore, the term free chlorine in public water systems typically refers to the concentration
of hypochlorous acid and hypochlorite anion. The term total chlorine as it pertains to water sanitation
practices usually refers to the amount of free chlorine plus chloroamines (sometimes called combined
chlorines) produced during the sanitation process. It is important to recognize that these compounds are
different from molecular chlorine even though the terminology is often used interchangeably.
2.2 SUMMARY OF HEALTH EFFECTS
Chlorine Gas. The principal targets of exposure to chlorine gas are the respiratory airways and the eyes.
Exposure can occur only by direct contact of inhaled chlorine gas with the respiratory epithelium or via
direct contact of the eyes with the gas. The skin seems to be a less sensitive target to direct contact with
chlorine gas possibly because it lacks the moisture of mucous membranes. The effects of acute-duration
exposures to high concentrations of chlorine have been known for almost a century, starting with its use
as a chemical weapon at Ypres, Belgium, during World War I. Additional information regarding the
effects of brief high-level exposures to chlorine has been collected from accidental exposures following
leaks during transport of tanks containing liquid chlorine, leaks from storage tanks, domestic accidents
involving bleach solutions, mishandling of chemicals used at swimming pools, and even accidents in high
school science experiments. These and many additional studies, including studies in volunteers exposed
to controlled concentrations of chlorine, indicate that exposures to 1–3 ppm produce mild irritation of the
nose that can be tolerated for about 1 hour; 5 ppm may produce eye irritation; headache and throat
irritation may occur at concentrations of 5–15 ppm; 30 ppm produces immediate chest pain, nausea and
vomiting, dyspnea, and cough; 40–60 ppm produces toxic pneumonitis and pulmonary edema; 430 ppm
usually causes death in 30 minutes, and 1,000 ppm is fatal within a few minutes. In most cases, death is
the result of pulmonary edema. Accidental releases of chlorine have affected adults and children, and a
few reports suggested that children might be more susceptible than adults to the effects of chlorine. This
may be due to the smaller diameter of the airways of children compared to adults.
The effects of exposure to chlorine seem to depend, at least above a certain minimal exposure
concentration, on the duration of exposure and exposure concentration, and the moisture content of the
surface contacted by the gas (i.e., the respiratory epithelium). Exposures to relatively low concentrations
11 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
of chlorine (95%) is scrubbed in the upper portion of the respiratory tract, whether breathing is through the nose or
through the mouth. With the exception of cough, substernal pain, and respiratory distress, the symptoms
occurring after exposure to moderate concentrations of chlorine generally subside within 24 hours.
Edema, observed following high exposures, is caused by marked alveolar capillary congestion followed
immediately by focal and confluent area of fluid with a high content of fibrinogen. Pulmonary edema
peaks in 12–24 hours and the resulting hypoxia further increases capillary permeability, which creates a
vicious cycle. Initially, the pulmonary fluid is interstitial, but if it overwhelms the capacity of the
lymphatic system to drain it, the alveoli become filled. A further complication is the formation of hyaline
membranes from the alveolar fluid with high-fibrinogen content, which along with developing areas of
atelectasis (collapse), and right to left shunting of blood, explains the poor oxygen diffusion with resultant
hypoxemia and later hypercapnea. Subjects surviving the acute phase of exposure to high concentrations
of chlorine may still be in danger of delayed death due to bronchial pneumonia or pneumonia. The
complications of chlorine inhalation fit the histological condition known as diffuse alveolar damage that
is associated with the clinical condition known as the adult respiratory distress syndrome.
Not all of the signs and symptoms exhibited by subjects exposed to moderate to high concentrations of
chlorine gas are caused directly by chlorine. In general, it is believed that effects such as nausea and
vomiting are reflex in origin, and headache and loss of consciousness are probably due to the hypoxia
caused by pulmonary edema. Leukocytosis is almost always found in subjects admitted to emergency
departments following exposure to high chlorine gas and is most likely a general response to
inflammation. Anxiety and changes in blood pressure and heart rate also are commonly mentioned in
case reports. While cardiovascular alterations can be due in part to a ventilation perfusion mismatch, they
may also represent a general response to the stress and anxiety of having been involved in a chemical
accident and being admitted to a health facility.
Prolonged exposures to relatively low concentrations of chlorine in occupational settings have not given
indications of respiratory or other health problems among the workers, but additional better-controlled
studies are necessary to add confidence to these early findings. Workers occasionally experience brief
episodes of high exposure (“gassing” incidents), in some cases to concentrations high enough to warrant a
visit to the emergency room. In some of these cases and also in some cases of high exposure of the
general population, long-term follow-up has shown persistent respiratory alterations that included airway
obstruction and reactive airway dysfunction syndrome (RADS). RADS is defined as an asthma-like
illness after a single acute exposure to a respiratory irritant in otherwise healthy individuals, characterized
12 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
by increased responsiveness to methacholine challenge. There are many factors that can play a role in
whether residual effects will be present, including exposure level and duration of exposure, medical
treatment following exposure, length of the follow-up, underlying respiratory disease, and smoking status.
A series of reports by Kilburn suggested that acute exposure to high concentrations of chlorine produced
long-term neurobehavioral effects (i.e., memory loss, slow reaction time, impaired balance, hearing loss,
visual alterations). No other study of chlorine-exposed subjects has included neurobehavioral testing, but
this could potentially be examined in animal models. It is not known whether exposure to chlorine gas
can affect reproduction or development in humans. Only one early study reported that pregnancy
outcome was not affected among female workers at a chlorine plant. There is also no relevant
information regarding effects of chlorine exposure on the immune system. A few studies of workers in
the chemical industry did not find any evidence that chlorine gas is carcinogenic. The EPA, the
International Agency for Research on Cancer (IARC), and the Department of Health and Human Services
(DHHS) have not classified chlorine gas as to its carcinogenicity.
The respiratory system is also the target of chlorine toxicity in animals. Animals exposed briefly to high
concentrations of chlorine gas have shown respiratory effects similar to those observed in humans, with
the added observations of severe gross and microscopic changes in the respiratory airways. Chlorine, in
relatively low concentrations (1–3 ppm), also induced histological alterations in the respiratory tract,
particularly the upper portion, in intermediate- and chronic-duration inhalation studies in animals. In
these studies, there was no indication that chlorine exposure affects reproductive parameters. No studies
are available that evaluated whether chlorine affects immunocompetence or the development of young
organisms. Chlorine gas was not carcinogenic in rats and mice exposed to up to 2.5 ppm for 2 years.
Hypochlorite Solutions. At very low pH (
13 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
woman who drank an unknown amount of bleach revealed esophageal and gastric mucosal erosions,
perforations at the gastroesophageal junction, and extensive necrosis of adjacent soft tissue. Aspiration of
hypochlorite bleach into the lungs following ingestion of bleach also has been reported as a cause of
death. The lethal dose of sodium hypochlorite in adults has been reported to be approximately 200 mL of
a solution containing 3–6% chlorine. No significant additional toxicities have been reported in humans
following oral exposure to hypochlorite. Two intermediate-duration studies in which volunteers were
exposed to known amounts of chlorine in water provided no evidence of adverse effects. In one of them,
consumption of water containing 5 mg/L chlorine (approximately 0.036 mg Cl/kg/day) had no significant
effect on hematology, serum chemistry, urinalysis, or additional physiological parameters. Another study
of limited scope showed that consumption of water containing 20 ppm chlorine (approximately 0.4 mg
Cl/kg/day) had no significant effect on serum lipids or serum levels of thyroid hormones. It is not known
whether oral exposure to chlorine can affect the immune and nervous systems, or reproduction or
development in humans. There are no studies of cancer in humans exposed to chlorine itself. Based on
inadequate evidence for carcinogenicity of hypochlorite salts in animals and no data from studies in
humans, a study determined that hypochlorite salts are not classifiable as to their carcinogenicity in
humans.
Direct contact of the skin with household chlorine bleach can cause skin irritation in humans. Although
sodium hypochlorite generally is not considered a contact sensitizer, several cases of allergic contact
dermatitis have been reported. Commercial household bleaches are prepared with sodium hydroxide and
are typically very alkaline; it is this property that may result in the irritant contact dermatitis. The limited
information regarding ocular effects of direct contact of the eye with hypochlorite solutions suggest that
splashes in the eye with house solutions of sodium hypochlorite rarely result in serious consequences.
For the most part, the results of oral and dermal studies of chlorine in animals support the observations in
humans. Studies in which hypochlorite bleach was placed in the esophagus of animals reproduced the
observations following high exposure in humans. Additional intermediate- and chronic-duration studies
that examined hematology and clinical chemistry parameters and conducted gross and microscopic
examination of tissues from rats and mice following exposure to chlorinated water provided little
evidence of chlorine-related toxicity. In the intermediate-duration studies, Sprague-Dawley rats,
F344 rats, and B6C3F1 mice were dosed for 90 days with up to 24.9, 85, and 39.2 mg Cl/kg/day,
respectively. In the chronic-duration studies, rats were exposed for 2 years to up to 14.4 mg Cl/kg/day
and mice to up 24.2 mg Cl/kg/day. Studies in animals have provided no evidence that exposure to
hypochlorite ions adversely affects the immune or nervous system, although an 8-week study in rats
14 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
reported alterations in some immune parameters of unknown toxicological significance (reduced delayed-
type hypersensitivity reaction, increased prostaglandin E2 synthesis by macrophages, and reduced
oxidative metabolism by macrophages following stimulation with phorbol myristate acetate). Exposure
of male and female rats to hypochlorite before and during breeding and of the females during gestation
and lactation did not cause reproductive effects in either sex or adverse developmental effects in the
offspring. Cancer bioassays in rats and mice have been negative except for equivocal evidence of
increased incidence of leukemia in female F344 rats in one study’s bioassay. It should be mentioned,
however, that one study considered the overall evidence only weakly supportive of an association
between the occurrence of mononuclear cell leukemia and the consumption of chlorinated water based on
the following: (1) the increase in leukemia was slight and not clearly dose-related, (2) there was no
decrease in tumor latency, and (3) the incidence in concurrent controls was less than in historical controls.
A limited number of studies of in vivo genotoxicity of hypochlorite ion provided negative results.
2.3 MINIMAL RISK LEVELS (MRLs)
Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for chlorine. An
MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an
appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are
derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive
health effect(s) for a specific duration within a given route of exposure. MRLs are based on
noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for
acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate
methodology does not exist to develop MRLs for dermal exposure.
Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a),
uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an
example, acute inhalation MRLs may not be protective for health effects that are delayed in development
or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic
bronchitis. As these kinds of health effects data become available and methods to assess levels of
significant human exposure improve, these MRLs will be revised.
15 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
Inhalation MRLs
• An MRL of 0.06 ppm has been derived for acute-duration inhalation exposure (14 days or less) to chlorine gas.
The effects of acute-exposure of humans and animals to chlorine have been well characterized (see
Sections 2.2 and 3.2.1.2). Chlorine is a sensory irritant (substance capable of eliciting sensory irritation)
and the most sensitive target for chlorine toxicity in humans and in animals is the respiratory system.
Information that could be used for quantitative risk assessment regarding effects from acute exposure of
humans to chlorine is available from studies of volunteers exposed to chlorine gas for 15 minutes to
8 hours (Anglen 1981; D’Alessandro et al. 1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al.
1998, 2003b). Some of these studies, as detailed below, also included sensitive individuals. Collectively,
the results of these studies suggest that brief exposures to concentrations of chlorine ≤0.5 ppm do not
cause sensory irritation or significant alterations in pulmonary function tests, but exposure to ≥1 ppm
chlorine can induce transient respiratory and eye irritation and slight alterations in pulmonary function
tests. Evaluations of soldiers gassed during World War I provide information on the effects of acute
exposure to very high concentrations of chlorine and also on potentially persistent effects of acute
exposure (Berghoff 1919; DOA 1933; Meakins and Priestley 1919). Similar information is available in
many reports of accidental exposures to chlorine gas of workers and members of the general population
(i.e., Agabiti et al. 2001; Agency for Toxic Substances and Disease Registry 1998; Bonetto et al. 2006;
CDC 1991, 2005; Chasis et al. 1947; Chester et al. 1977; Hasan et al. 1983; Schönhofer et al. 1996;
Sexton and Pronchik 1998; Weill et al. 1969). In both the war cases and the accidental exposures to
chlorine gas, the concentrations of chlorine were generally not known. These high exposure cases have
provided data on respiratory effects and on additional signs and symptoms of intoxication with chlorine
that are not due to a direct action of chlorine, but that probably represent reflex responses and/or general
responses to inflammation and stress that were caused by products of chlorine’s reaction with bodily
fluids. Some of these responses include nausea, vomiting, headache, anxiety, alterations in blood
pressure, and leukocytosis.
The acute-duration database in animals is extensive, and includes a great number of studies conducted
after the use of chlorine as a chemical weapon during World War I (for review, see DOA [1933] and
Withers and Lees [1985b]). Most of the early studies provide information regarding lethal concentrations
of chlorine as well as descriptions of the pathology of the respiratory tract caused by exposure to
relatively high concentrations of chlorine. Although qualitatively informative, the early data do not meet
current guidelines for use in quantitative risk assessment. More recent studies in animals, mainly rodents,
16 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
have confirmed the earlier findings regarding sensory irritation and pathological changes in the
respiratory tract (Barrow and Smith 1975; Buckley et al. 1984; Demnati et al. 1995; Jiang et al. 1983;
Leustik et al. 2008; Tian et al. 2008; Yildirim et al. 2004). In general, morphological alterations in the
nasal mucosa of rats and mice occurred with chlorine concentrations >5 ppm. Specific lowest-observed-
adverse-effect levels (LOAELs) for sensory irritation in rodents are not available. However, in response
to exposure to irritant substances, a reflex mechanism allows rodents to decrease the respiratory rate as a
protective response (Alarie 1973). The concentration of the irritant that induces a 50% decrease in
respiratory rate has been termed RD50 and is commonly used to compare the irritant potencies of
chemicals. This reflex reaction has also been demonstrated in humans, dogs, and cats (Alarie 1973).
Acute-duration inhalation studies provided very little information regarding end points other than those
involving the respiratory system. Body weight loss, which is due to reduced food consumption, was
reported in some studies (Dodd et al. 1980; Jiang et al. 1983).
Evaluation of the acute-duration inhalation database summarized above indicates that sensory irritation
and pulmonary function in humans are the most sensitive end points for exposure to chlorine and will
serve as the basis for derivation of an acute-duration inhalation MRL for chlorine. These findings were
reported in a group of studies that can serve as co-principal studies (Anglen 1981; D’Alessandro et al.
1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 1998, 2003b). A detailed description of
these studies is provided in Appendix A.
Collectively, this group of studies provides evidence of sensory irritation and transient pulmonary
changes occurring in humans exposed to 1 ppm chlorine for up to 8 hours/day. The pulmonary changes
indicated increased airway resistance and reduced air flow. No such changes were reported in volunteers
exposed to 0.5 ppm chlorine (0.4 ppm in the D’Alessandro et al. [1996]) study. The longest exposure
duration was 8 hours (Anglen 1981; Rotman et al. 1983). These studies also included sensitive
individuals: an atopic subject in the study by Rotman et al. (1983), subjects showing methacholine
hyperresponsiveness in the study by D’Alessandro et al. (1996), and subjects exhibiting seasonal allergic
rhinitis (Shusterman et al. 1998). Also of significance is the fact that Rotman et al. (1983) reported that
exposure to 1 ppm for 8 hours induced greater changes in pulmonary function tests than exposure to the
same concentration for 4 hours, suggesting that the response was related to duration in addition to
concentration. Given this information, an acute-duration inhalation MRL for chlorine can be derived by
duration adjustment of the no-observed-adverse-effect level (NOAEL) of 0.5 ppm for continuous
exposure (0.5 ppm x 8 hours/24 hours = 0.167 ppm) (8 hours was the longest period of exposure for
which there is information). Although sensitive individuals were tested in some of these studies, the
17 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
number of individuals tested at the region of the NOAEL (0.4–0.5 ppm) was small. Therefore, an
uncertainty factor of 3 is used to account for sensitive populations. The resulting acute-duration
inhalation MRL for chlorine is 0.06 ppm (0.167 ppm/3).
• An MRL of 0.002 ppm has been derived for intermediate-duration inhalation exposure (15– 364 days to chlorine gas.
No human studies were available that could serve as the basis for derivation of an intermediate-duration
inhalation MRL. The animal database for intermediate-duration exposure to chlorine is limited to two
studies. In one study, male and female F344 rats were exposed to 0, 1, 3, or 9 ppm chlorine 6 hours/day,
5 days/week for 6 weeks (Barrow et al. 1979). In the other study, male and female F344 rats were
exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 62 days (Kutzman 1983). Aside
from a reduction in final body weight of approximately 11% relative to controls in female rats exposed to
0.5 ppm chlorine (most likely due to reduced food consumption) in the Kutzman (1983) study, the most
sensitive target for chlorine exposure was the respiratory tract. Barrow et al. (1979) described
inflammation of the nasal turbinates in rats exposed to ≥1 ppm chlorine, whereas loss of cilia and
epithelium in the trachea was seen in rats exposed to ≥0.5 ppm in the Kutzman (1983) study. No
NOAELs for respiratory effects were established in either study. Since incidences of animals with
respiratory lesions were presented in the Kutzman (1983) study, but not in the Barrow et al. (1979) study,
the Kutzman (1983) study was selected as the principal study for derivation of an intermediate-duration
inhalation MRL for chlorine (more complete descriptions of the end points evaluated and the reported
results in these studies can be found in Section 3.2 and Appendix A).
There were no significant exposure-related increases in the incidences of animals with histological lesions
in any of the examined tissues with the exception of a loss of cilia in the trachea (Kutzman 1983). The
incidences of slight to moderate loss of tracheal cilia were 1/23, 12/23, 4/23, and 13/23 in the 0, 0.5, 1.5,
and 5 ppm exposure groups, respectively. Although the incidence for this lesion in the mid-exposure
group was not significantly different from the control incidence, a statistically significant (p=0.0055)
Cochran-Armitage trend test for these data can be demonstrated. However, when attempts were made to
apply dose-response models to the data, no adequate fits of EPA Benchmark Dose Software (BMDS)
models to the data were obtained (p-values for chi-square goodness of fit statistics were
18 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
LOAEL[HEC] = LOAEL[ADJ] x RGDRTB
where: LOAEL[ADJ] = 0.5 ppm x 6/24 hours x 5/7 days = 0.09 ppm and RGDRTB = ratio of the regional gas dose in rats to that of humans for the tracheobronchial region
RGDRTB = (VE/SATB)A / (VE/SATB)H
where: VE = minute volume (0.137 L/minute for rats, 13.8 L/minute for humans [EPA 1994a]) and SATB = surface area of the tracheobronchial region (22.5 cm2 for rats and 3,200 cm2 for humans
[EPA 1994a]) LOAEL[HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm2) / (13.8 L/minute/3,200 cm2) = 0.14 ppm
Applying an uncertainty factor of 90 (3 for extrapolation from animals to humans with dosimetric
adjustment, 3 for the use of a minimal LOAEL, and 10 for human variability) to the LOAEL[HEC] yields
an intermediate-duration inhalation MRL of 0.002 ppm for chlorine.
• An MRL of 0.00005 ppm has been derived for chronic-duration inhalation exposure (365 days or more) to chlorine gas.
There is no information regarding chronic-duration exposure of the general population to chlorine
because this type of exposure occurs only in occupational settings. There are few studies of chronically-
exposed workers in which there is some documentation regarding exposure levels and in which there is no
evidence, at least explicitly mentioned in the studies, of the workers having being subjected to acute
episodes of high exposure or “gassing” incidents. One of these studies involved 600 workers from
25 plants producing chlorine subjected to an evaluation of medical and occupational histories, blood and
urine tests, pulmonary function tests, and electrocardiogram (Patil et al. 1970). Exposure data were
available for 332 workers and showed a time-weighted average (TWA) 8-hour mean of 0.15±0.29 ppm
(range, 0.006–1.42 ppm). Evaluation of the 332 workers who had exposure data showed that none of the
end points examined (those subjected to recall or measured) showed a dose-response relationship. The
mean concentration of 0.15 ppm may be considered a NOAEL for the study, but limitations such as
unclear analytical methodology, no clear definition of the case/control populations, and insufficient detail
regarding the method of analysis render the NOAEL questionable. A respiratory health assessment of
392 male pulp mill workers exposed predominantly to a mean 8-hour TWA of 0.18 ppm chlorine (other
possible exposures included, sulfur dioxide, hydrogen sulfide, and methylmercaptan, in addition to
various particulates) found that, relative to a control group, the pulp mill workers complained more
frequently of usual phlegm, wheeze without cold, and chest illness (Enarson et al. 1984). However, the
most significant finding was that a subgroup of nonsmokers (n=4) had a significantly lower fixed
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19 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
expiratory flow rate at 25–75% vital capacity (FEF25–75%) and forced expiratory volume in
1 second/forced vital capacity (FEV1/FVC) ratio than the control workers. Given the small number of
workers involved and the possibility of exposure to multiple chemicals, the validity of the 0.18 ppm as an
effect level is questionable. An additional issue to consider is that neither one of these studies seemed
adequate to detect possible mild alterations in the nasal cavity, a sensitive target of chlorine exposure in
humans and animals, as described in Sections 2.2 and 3.2.1.2. Due to the limitations mentioned above,
these long-term studies are insufficient for quantitative risk assessment.
There are only two chronic-duration inhalation studies of chlorine in animals. One is a 1-year study in
monkeys (Klonne et al. 1987) and the other is a 2-year bioassay in rats and mice (Wolf et al. 1995). Both
studies tested similar concentrations of chlorine (up to 2.3 ppm in monkeys and 2.5 ppm in rats and mice)
and evaluated multiple end points including respiratory tract histopathology, hematology, and clinical
chemistry. In both studies, the upper respiratory tract was the target for chlorine toxicity. In general,
lesions were less severe in the monkeys than in rats and mice, but extended more distally in the
respiratory tract. In rats and mice, an increased incidence of minimal to moderate alterations occurred
with the lowest exposure concentration tested, 0.4 ppm chlorine. In general, the nasal lesions were site-
specific, but the severity and/or incidence were not always concentration-dependent. Lesions observed
included respiratory and olfactory epithelial degeneration, septal fenestration, mucosal inflammation,
respiratory epithelial hyperplasia, squamous metaplasia, and goblet cell hypertrophy and hyperplasia, and
secretory metaplasia of the transitional epithelium of the lateral meatus. For the most part, monkeys
exhibited only mild concentration-related respiratory epithelial hyperplasia with focal loss of cilia over
the range of concentrations tested (0, 0.1, 0.5, and 2.3 ppm) and showed no evidence of the major nasal
lesions seen in rats and mice. These differences are probably related to species-specific respiratory-tract
airflow characteristics (Ibanes et al. 1996), which in turn, are determined by anatomical differences.
Moreover, rats and mice are obligatory nose breathers with a greater surface-area-to-volume ratio of the
upper respiratory tract than primates. Therefore, exposure of rodents and primates to equal concentrations
for equal amounts of time will likely result in greater pathological changes in the nasal area of the rodent
(Barrow et al. 1979). It appears, therefore, that primates are a better model to evaluate potential
respiratory effects in humans than rodents. For these reasons, the study in monkeys (Klonne et al. 1987)
was selected for deriving a chronic-duration inhalation MRL for chlorine.
In the principal study, male and female Rhesus monkeys (4/sex/exposure level) were exposed to 0, 0.1,
0.5, or 2.3 ppm chlorine 6 hours/day, 5 days/week for 1 year (Klonne et al. 1987). The only treatment-
related histopathological effects consisted of focal epithelial hyperplasia characterized by increased cell
20 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
numbers and loss of cilia and goblet cells in the respiratory epithelium of the nose and trachea. The
affected areas of the nasal passages showed hypercellularity with loss of goblet cells and cilia. In some of
these areas, the nuclei showed altered polarity. Lesions were more frequent on the angular margins of the
turbinates and less frequent on the lateral wall or septum adjacent to these margins. In some cases, the
respiratory epithelial hyperplasia was associated with mild suppurative inflammatory response. Lesions
in the trachea resembled those in the nose, but were less severe and involved only a small circumferential
section of the ventral and ventrolateral trachea. The combined incidences of hyperplasia in the nasal
epithelium with loss of goblet cells and cilia, characterized as trace and mild in males and females, were
1/8, 3/8, 6/8, and 8/8 in the control, 0.1, 0.5, and 2.3 ppm exposure groups, respectively. The exposure
concentration of 0.1 ppm is considered a minimal LOAEL for nasal lesions in monkeys.
Incidence data for nasal lesions in male and female monkeys exposed to chlorine gas (Klonne et al. 1987)
were analyzed using the benchmark dose (BMD) approach for MRL derivation (further details of the
modeling are presented in Appendix A) (EPA 2008a). Models in the EPA BMDS (version 1.4.1) (i.e.,
Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, and Weibull) were fit to
the nasal lesion data to determine potential points of departure for the MRL. A Quantal linear model
provided the best fit to the data. From this model, the predicted exposure concentration associated with a
10% extra risk (BMC10) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on
this concentration (BMCL10) was 0.02 ppm. The monkey BMCL10 served as the point of departure for the
chronic-duration MRL, after it was converted to a HEC (BMCL10[HEC]) using the EPA cross-species
dosimetric methodology (EPA 1994a) for a category 1 gas, as follows:
BMCL10[HEC] = BMCL10[ADJ] x RGDRET
where: BMCL10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and RGDRET = ratio of the regional gas dose in rats to that of humans for the extrathoracic region
RGDRET = (VE/SAET)A / (VE/SAET)H
where: VE = minute volume 2.1 m3/day for monkeys, calculated using the allometric equation for
monkeys in EPA (1988) assuming a body weight of 7 kg for Rhesus monkeys with nasal cavity surface area of 62 cm2 (Gross and Morgan 1991); 20 m3/day for humans (EPA 1994a) and
SAET = 62 cm2 surface area of the nasal cavity in Rhesus monkeys weighing 7 kg (Gross and Morgan 1991); 200 cm2 for humans (EPA 1994a)
RGDRET = (2.1 m3/day / 62 cm2) / (20 m3/day / 200 cm2) = 0.34
21 CHLORINE
2. RELEVANCE TO PUBLIC HEALTH
BMCL10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm
Applying an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric
adjustment and 10 for human variability) to the BMCL10[HEC] yields a chronic-duration inhalation MRL of
0.00005 ppm for chlorine.
For the purp